The emerging role of ?-synuclein truncation in aggregation and disease

?-Synuclein (?syn) is an abundant brain neuronal protein that can misfold and polymerize to form toxic fibrils coalescing into pathologic inclusions in neurodegenerative diseases, including Parkinson's disease, Lewy body dementia, and multiple system atrophy. These fibrils may induce further ?syn misfolding and propagation of pathologic fibrils in a prion-like process. It is unclear why ?syn initially misfolds, but a growing body of literature suggests a critical role of partial proteolytic processing resulting in various truncations of the highly charged and flexible carboxyl-terminal region. This review aims to 1) summarize recent evidence that disease-specific proteolytic truncations of ?syn occur in Parkinson's disease, Lewy body dementia, and multiple system atrophy and animal disease models; 2) provide mechanistic insights on how truncation of the amino and carboxyl regions of ?syn may modulate the propensity of ?syn to pathologically misfold; 3) compare experiments evaluating the prion-like properties of truncated forms of ?syn in various models with implications for disease progression; 4) assess uniquely toxic properties imparted to ?syn upon truncation; and 5) discuss pathways through which truncated ?syn forms and therapies targeted to interrupt them. Cumulatively, it is evident that truncation of ?syn, particularly carboxyl truncation that can be augmented by dysfunctional proteostasis, dramatically potentiates the propensity of ?syn to pathologically misfold into uniquely toxic fibrils with modulated prion-like seeding activity. Therapeutic strategies and experimental paradigms should operate under the assumption that truncation of ?syn is likely occurring in both initial and progressive disease stages, and preventing truncation may be an effective preventative strategy against pathologic inclusion formation.